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International Journal of Hypertension

Volume 2011, Article ID 916310, 7 pages
doi:10.4061/2011/916310

Review Article
Oxidative Stress and Vascular Damage in Hypertension:
Role of Angiotensin II

Agostino Virdis, Emiliano Duranti, and Stefano Taddei

Department of Internal Medicine, University of Pisa, 56100 Pisa, Italy

Correspondence should be addressed to Agostino Virdis, a.virdis@med.unipi.it

Received 18 February 2011; Accepted 16 March 2011

Academic Editor: Isabella Sudano

Copyright © 2011 Agostino Virdis et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Reactive oxygen species are oxygen derivates and play an active role in vascular biology. These compounds are generated within
the vascular wall, at the level of endothelial and vascular smooth muscle cells, as well as by adventitial fibroblasts. In healthy
conditions, ROS are produced in a controlled manner at low concentrations and function as signaling molecules regulating
vascular contraction-relaxation and cell growth. Physiologically, the rate of ROS generation is counterbalanced by the rate of
elimination. In hypertension, an enhanced ROS generation occurs, which is not counterbalanced by the endogenous antioxidant
mechanisms, leading to a state of oxidative stress. In the present paper, major angiotensin II-induced vascular ROS generation
within the vasculature, and relative sources, will be discussed. Recent development of signalling pathways whereby angiotensin
II-driven vascular ROS induce and accelerate functional and structural vascular injury will be also considered.

1. Introduction including collagen type I and III, elastin, and fibronectin. An

Hypertension is associated with increased peripheral resis-
tance, resulting predominantly from functional, structural,
and mechanical alterations at the level of small-resistance
arteries. Functional alterations, which include an impaired
endothelial function, are mainly assessed as an impaired ace-
tylcholine-induced, endothelium-dependent relaxation. Vas-
cular structural changes include vascular remodeling, sec-
ondary to an increased cell growth, cell migration, and
low-grade vascular inflammation [1, 2]. In particular, an
increased media-to-lumen ratio (M/L) may result from a re-
duced outer diameter that narrows the lumen without net
growth (eutrophic remodeling) or from a thicker media
encroaching on the lumen (hypertrophic remodeling) [1, 2].
Another hallmark of hypertension-induced structural
abnormalities is represented by changes in the mechanical
properties of arteries, with particular regard for increased
stiffness [3]. Vascular fibrosis is critically important in the
determinism of vascular structural modifications, and it
involves changes in extracellular matrix (ECM) components,
increase in collagen and fibronectin and a decrease in elastin
contents have been shown in the media of small arteries from
hypertensive animals [3–5].
It is widely accepted that angiotensin (Ang) II, tradition-
ally involved in modulating blood pressure and electrolyte
homeostasis, is also greatly implicated in the pathogenesis
of endothelial dysfunction and vascular remodeling [6–8].
This concept is strengthened by the evidence that chronic
AT1 receptor blockade is able to correct the altered structure
and endothelial dysfunction of subcutaneous resistance small
vessels from patients with essential hypertension whereas
the β-receptor blockade has no effect, despite similar blood
pressure lowering effect [9]. Major mechanisms whereby
Ang II exerts vascular damage include generation of reactive
oxygen species (ROS) and stimulation of redox-dependent
signalling pathways [6, 10, 11].
The present review will focus on major Ang II-induced
vascular ROS generation and on recent development of sig-
nalling pathways whereby Ang II-driven vascular ROS induce
and accelerate functional and structural vascular injury.
2 International Journal of Hypertension
2. Reactive Oxygen Species in Vascular Wall
ROS are ubiquitous reactive derivatives of O2 metabolism
found in the environment and in all biological systems. ROS
are implicated in many intracellular signaling pathways lead-
ing to changes in gene transcription and protein synthesis
and consequently in cell function. Within the cardiovascular
system, ROS play a crucial physiological role in maintaining
cardiac and vascular integrity and a pathophysiological
role in cardiovascular dysfunction associated with several
clinical conditions, including hypertension [12, 13]. The
most important ROS detectable within the vasculature
include the superoxide anion (• O2 − ), hydrogen peroxide
(H2 O2 ), hydroxyl radical (• OH), and the reactive nitrogen
species peroxynitrite (ONOO− ), which have been regarded
as a nasty, life-threatening, and destructive oxygen-derived
toxicant. In healthy conditions, ROS are produced in a
controlled manner at low concentrations and function as sig-
naling molecules regulating vascular contraction-relaxation
and cell growth [14]. Physiologically, ROS generation is
tightly regulated by endogenous cellular antioxidants, which
include superoxide dismutase (SOD), catalase, thioredoxin,
glutathione, and antioxidant vitamins. In physiological con-
ditions, the rate of ROS generation is counterbalanced by
the rate of elimination. In contrast, under pathological
conditions, such as hypertension, ROS are produced in con-
centrations that cannot be controlled by the usual protective
antioxidant mechanisms employed by the cells, leading to
a state of oxidative stress [13]. Indeed, when produced in
excess, • O2 − reacts with nitric oxide (NO) to produce a
dramatic concentration of the toxic ONOO− which pro-
motes a variety of negative effects on cellular function. These
include alteration of transcription factors, kinases, protein
synthesis, and redox-sensitive genes, which in turn influence
endothelial function, increase vascular contractility, vascu-
lar smooth muscle cell growth and apoptosis, monocyte
migration, lipid peroxidation, inflammation, and increased
deposition of ECM proteins, all major processes deeply
involved in the pathogenesis and progression of vascular
damage in cardiovascular disease [15, 16].
3. Major Sources of ROS Generation in
the Vascular Wall
Vascular ROS may be produced at the level of endothelial,
as well as smooth muscle and adventitial cells, and can be
generated by several enzymes. As concerns hypertension-
related vascular disease, major sources of ROS are xanthine
oxidase, uncoupled endothelial NO synthase, NAD(P)H
oxidase, and cyclooxygenase (COX) [17]. The role of COX
in the Ang II-mediated oxidant excess will be described later.
The xanthine oxidase system, detectable in the vascular
endothelium, catalyses the oxidation of hypoxanthine and
xanthine to form • O2 − . Major demonstrations of the role
of xanthine oxidase-system concern the setting of ischemia-
reperfusion injury and heart failure. Nevertheless, some
experimental reports also indicate an involvement of such
complex in hypertension. In mesenteric small vessels from
spontaneously hypertensive rats (SHR), an enhanced activity
of xanthine oxidase was documented [18]. Beyond its
effect within the vascular wall, an active role of xanthine
oxidase has been also documented in the kidney from SHR
or Dahl salt-sensitive rats. Usually, the xanthine oxidase
enzymatic system is inhibited by allopurinol. Of note,
chronic allopurinol administration in SHR, while abrogating
the renal xanthine oxidase-related ROS generation, failed
to reduce blood pressure values, suggesting that, at least in
such animal model of disease, the increased renal ROS pro-
duction is a mere consequence of hypertension rather than
a pathogenetic factor [19]. This concept is supported by the
findings that in these animals chronic allopurinol intake is
also associated with an amelioration of cardiac hypertrophy
[20].
Endothelial nitric oxide synthase (eNOS), the enzymatic
system constitutively delegated to produce NO, can also gen-
erate ROS in those conditions characterized by deficiency
of the substrate arginine or the cofactor tetrahydrobiopterin
(BH4 ). This process, which has been called “NOS uncou-
pling,” implies that the physiological activity of the enzyme
for NO production is decreased and switched to the NOS-
dependent • O2 − generation. eNOS uncoupling has been
documented in several pathological conditions, including
diabetes [21], hyperhomocysteinemia [22], and hyperten-
sion [23]. eNOS uncoupling has been demonstrated in
DOCA salt-induced hypertensive mice. In this animal model,
the critical step in this uncoupling seems to be oxidation of
BH4 by ONOO− , reducing the bioavailability of this critical
cofactor [23]. The activity of eNOS uncoupling as ROS
source in hypertension is strengthened by human evidence in
diabetic and hypertensive patients, where endothelial oxidant
excess was dramatically reduced by administration of the
precursor of BH4 [24, 25].
A large body of evidence indicated that NAD(P)H
oxidase represents the major source of ROS in the vascu-
lar wall. The activation of such enzymatic system, which
utilises NADH/NADPH as electron donor to reduce molec-
ular oxygen and generate • O2 − , requires the assembly
of cytosolic (p47phox, p67phox) and membrane-bound
(gp91phox/Nox1/Nox4 and p22phox) subunits to form a
functional enzyme complex [17]. In the vasculature the
NAD(P)H oxidase complex is at least partly preassembled,
as a significant proportion of NAD(P)H oxidase subunits
are colocalized intracellularly in endothelial cells [17]. It is
widely recognized that NAD(P)H oxidase is the primary
source of • O2 − in the vasculature [15], and it is functionally
active either in the endothelium or in the media and adven-
titia as well [15]. Within the vascular wall, all the NAD(P)H
oxidase subunits are expressed, to varying degrees [15, 17].
4. Role of Angiotensin II on ROS Generation
within the Vasculature
A large body of evidence supports a crucial role for ROS
production, particularly from NAD(P)H oxidase, in vascular
injury which characterizes the hypertensive disease. Ang II
represents one of the major vasoactive peptides, together
International Journal of Hypertension
with cytokines and growth factors, involved in the regulation
and activation of NAD(P)H oxidase. Ang II stimulates activa-
tion of NAD(P)H oxidase, increases expression of NAD(P)H
oxidase subunits, and induces ROS generation in vascular
smooth muscle cells, endothelial cells, adventitial fibroblasts,
and intact arteries as well [15, 26]. Experimental reports
documented that Ang II may exert such effects via AT1
receptors. Of note, ROS may regulate AT1 receptor gene
expression, which in turn modulates ROS generation, thus
perpetuating a vicious circle [27]. Molecular mechanisms
and signaling pathways whereby Ang II-derived NAD(P)H
oxidase activation leads to vascular cell oxidation are beyond
the scope of this report and, therefore, the reader is directed
to many excellent reviews focusing on these aspects [6, 17].
The strict crosstalk between Ang II and NAD(P)H oxi-
dase is confirmed by in vivo studies. Thus, in Ang II-infused
hypertensive rats, NAD(P)H oxidase subunit expression and
activity are increased, and administration of an NAD(P)H
oxidase inhibitor reduces vascular • O2 − generation [28, 29].
More recently, it was demonstrated that chronic administra-
tion of apocynin, a selective inhibitor of NAD(P)H oxidase,
prevents the increase in media-to-lumen ratio, an index
of vascular remodeling, as well as endothelial dysfunction
and collagen deposition at the level of mesenteric resistance
arteries from Ang II-infused mice [30]. These data suggest
that activation of vascular NAD(P)H oxidase plays an impor-
tant role in vascular functional and structural changes that
accompany development of hypertension in Ang II-infused
mice. Of note, in this study, apocynin, which, abolishing
the Ang II-induced increase of vascular NAD(P)H oxidase
activity, was able to attenuate the systolic blood pressure
rise induced by Ang II [30]. These findings demonstrate
that NAD(P)H oxidase inhibition leads to blood pressure
reduction in an Ang II-dependent hypertensive murine
model and support the concept that NAD(P)H oxidase-
derived • O2 − plays a role in the Ang II-induced blood pres-
sure elevation. It is worth noting that in this experimental
condition, apocynin, while only partially reducing blood
pressure, totally abolished the Ang II-mediated NAD(P)H
oxidase increased activity, thus suggesting that, at least in
mice, redox-independent pathways also underlie Ang II-
induced blood pressure elevation. These findings, obtained
by pharmacological doses of exogenous Ang II, are supported
by other reports assessing the role for the endogenous renin-
angiotensin system in increasing ROS production during
hypertension. In the 2-kidney 1-clip model of renovascular
hypertension (a model characterized by a high activation
of the renin-angiotensin system), endothelial dysfunction
was associated with an NAD(P)H oxidase-derived increased
•
O2 − production, a condition which in part participates in
blood pressure elevation in blood pressure [31]. In salt-
sensitive Dahl rats, another animal model of hypertension
characterized by activation of the local renin-angiotensin
system, chronic administration with an Ang II receptor
blocker dramatically reduced vascular • O2 − production [32].
Of note, in animal model of salt-sensitive hypertension,
treatment with a gp91phox-containing NAD(P)H oxidase
inhibitor also prevented the increased vascular • O2 − pro-
duction together with the expression of proinflammatory
3
molecules, thus supporting the concept of a linkage between
renin-angiotensin system, NAD(P)H oxidase activity, and
vascular inflammation [33]. Importantly, the deleterious
effect by Ang II-derived NAD(P)H oxidase activity on
vasculature is not dependent on blood pressure elevation.
Indeed, it was documented that in an animal model of Ang
II-hypertension, production of H2 O2 , while essential for Ang
II-mediated vascular changes, had no significant impact on
blood pressure [34].
There is also evidence for ROS involvement in the hy-
pertension-related vascular disease independent of Ang II
actions. Indeed, it has been suggested that endothelin-1
(ET-1) is implicated in the development of vascular changes
through the ROS generation via NAD(P)H oxidase activa-
tion [35]. Interestingly, the ET-1-mediated enhanced ROS
production can affect vascular structure and function inde-
pendently of blood pressure modifications. Direct infusion
of ET-1 can increase NAD(P)H oxidase-dependent • O2 −
production, which is not significantly related to the devel-
opment of hypertension [36]. Recently, an animal model
of transgenic mice overexpressing human preproET-1 gene
specifically in blood vessel endothelium was generated. This
is an useful model to investigate the role of endothelium-
generated ET-1 on the endothelial function and vascular
structure of small resistance arteries. These animals exhibited
3-fold higher vascular tissue ET-1 mRNA and 7-fold higher
ET-1 plasma levels than did wild-type mice but no significant
elevation in blood pressure [37]. Despite the absence of
significant blood pressure elevation, transgenic mice exhib-
ited marked hypertrophic remodeling and oxidant excess-
dependent endothelial dysfunction of resistance vessels,
altered ET-1 and ET-3 vascular responses, and significant
increases in ETB expression compared with wild-type lit-
termates. Moreover, transgenic mice generated significantly
higher oxidative stress, possibly through increased activity
and expression of vascular NAD(P)H oxidase [37]. Using
a transgenic approach, these findings represent the demon-
stration that endothelium-secreted human ET-1 induces
vascular remodeling and endothelial dysfunction in the
absence of significant increases in blood pressure, as also
evidenced above for Ang II actions.
In conclusions, these data unambiguously underscore the
concept that Ang II exerts several pleiotropic deleterious
vascular effects, including functional and structural changes,
through NAD(P)H oxidase-derived ROS generation, an
effect which does not necessarily occur as a consequence of
blood pressure elevation.
5. Role of Cyclooxygenase on Ang II-Induced
Vascular Damage
In the last decade, a growing literature provided evidence that
a major pathway involved in vascular disease is cyclooxyge-
nase (COX) activity [38]. Indeed, COX metabolizes arachi-
donic acid from membrane-bound phospholipids into the
unstable intermediate PGH2 , which, in turn, is converted
by an array of downstream enzymes to form a variety of
bioactive prostaglandins (PGs) and thromboxane (TX) A2 ,
4 International Journal of Hypertension
collectively termed prostanoids [39]. These have been con-
sidered autacoids mediating a variety of responses in the car-
diovascular system, including modulation of vascular tone
and structure and inflammatory responses. Under physiolog-
ical conditions, prostacyclin (PGI2 ) is the major prostanoid
identified and released by endothelial cells mediating several
protective effects on the vascular wall, including relaxation
and inhibition of platelet aggregation and adhesion [40]. The
predominant opponent of PGI2 is TXA2 , specifically acting
on thromboxane-prostanoid (TP) receptors mainly located
on smooth muscle cells where it causes vasoconstriction
[41]. Under pathological conditions, such as inflammation
or atherosclerosis, the PGI2 production decreases, and COX-
derived vasoconstrictor substance release, including TXA2 ,
becomes predominant. Two distinct COX isoenzymes, COX-
1 and COX-2, have been described. Although COX-1 is
constitutively expressed to produce physiologically relevant
prostanoids, COX-2 is regarded as an inducible isoform,
which can be rapidly upregulated by a number of stimuli, A
direct interaction between Ang II and the COX pathway has
been described. Thus, a direct interaction between Ang II and
COX-2 pathway was documented in in vitro studies, either
in vascular smooth muscles (VSMCs) or endothelial cells.
Ohnaka et al. [42] observed that Ang II dose-dependently
increased the expression of COX-2 mRNA in cultured rat
VSMCs. This effect was totally abolished by the AT1 receptor
antagonist losartan, by the mitogen-activated protein kinase
(MAPK) kinase-1 inhibitor, and by the p38 MAPK inhibitor.
A similar possibility was hypothesized by Young et al.
[43], who documented that a COX-2-derived prostanoid,
possibly TXA2 , may contribute to VSMC hyperplasia in
rat aortic injury or pathophysiological conditions associated
with elevated levels of TNF-α or Ang II. In this study, the
activation of MAP kinase was confirmed to be implicated as
a signaling pathway for COX-2 gene transcription and pro-
liferative response of VSMCs to Ang II. An increased COX-
2 expression secondary to Ang II incubation was confirmed
also in cultured human VSMCs [44]. Taken together, these
in vitro animal and human reports provide evidence that
Ang II-mediated activation of AT1 receptors plays a crucial
role in triggering multiple biological responses in VSMCs,
including cell growth and proliferation, via increased COX-
2 expression. The relationship between Ang II and COX-
2 were extended in vivo. In a rat model of Ang II-induced
hypertension, it was demonstrated that Ang II-mediated
vascular lesions were associated with increased expression of
COX-2 in the media of coronary arteries [45]. However, these
findings were not confirmed when the interaction between
Ang II and COX-2 were investigated in mREN2 rats, a trans-
genic animal model of hypertension characterized by Ang
II-induced vascular and tissue injury [46]. In such animals,
the authors explored whether COX-derived prostanoids were
involved in the pathogenesis of Ang II-induced vascular
injury, in myocardium and kidney. The main finding of this
report was that neither nonselective COX inhibitor nor the
COX-2 selective blocker was able to prevent Ang II-induced
vascular and tissue damage. Moreover, myocardial and renal
COX-2 mRNA expressions were decreased in mREN2 rats.
Therefore, these results seem to exclude, at least in this
particular transgenic animal model, a central role by COX in
the pathogenesis of ANG II-induced vascular or end-organ
damage. Of note, the interpretation of these findings deserve
caution if we consider that this particular transgenic animal
model does not reproduce physiological conditions. Never-
theless, when Ang II and COX interaction is investigated in
resistance arteries, in more physiological conditions, a pivotal
role of COX-1 on Ang II-mediated vascular changes, instead
of COX-2, emerged. Thus, we documented that in mesenteric
small vessels from Ang II-infused mice, COX-1 inhibition
as well as TP receptor antagonist similarly improved the
blunted endothelium-dependent relaxation to acetylcholine
while COX-2 inhibition was ineffective [8]. In addition,
a COX-2 downregulation and a simultaneous induction
of COX-1 expression and staining in Ang II-vessels were
detected. Concomitantly, the NAD(P)H oxidase apocynin,
while normalizing endothelial function, failed to modify
the COX-2 downregulation and COX-1 upregulation [8].
Overall, these results demonstrate the participation of COX-
1 isoenzyme in the development of functional alterations of
resistance arteries from Ang II-infused mice. As summarized
in Figure 1, it was proposed that Ang II is associated to COX-
1 overexpression and COX-2 downregulation while Ang II-
mediated ROS production stimulates COX-1 activity, but not
overexpression, to produce a contracting prostanoid, acting
as an agonist on TP receptors [8]. Of note, in this report
COX-1 blockade improved only in part the Ang II-induced
endothelial dysfunction, thus confirming the presence of a
residual direct and specific COX-1-independent effect of Ang
II on the vascular wall [8].
Ang II plays also a crucial role in inducing mechanical
changes of arteries, with particular regard for increased
stiffness, and in determining changes in ECM components
within the vascular wall [3–5, 47]. Indeed, an increased col-
lagen and fibronectin depositions, together with a decreased
elastin content, have been described in the media of small
arteries from Ang II-infused animals [4, 5, 47]. In this con-
text, experimental observations strongly suggest a predomi-
nant role of COX-1-derived activators of TP receptors in the
development/progression of vascular atherosclerosis [48].
Therefore, a direct interaction between Ang II and COX-
1 pathway can be hypothesized as one of the mechanisms
whereby Ang II induces vascular structural changes. In a very
recent report, this possibility has been investigated in our
laboratory, by utilizing two different experimental method-
ologies, such as the employment of selective COX isoforms
inhibitors, chronically administered to Ang II-treated mice,
and the utilization of homozygous mice carrying a targeted
disruption of COX-1 gene. In murine mesenteric small
vessels, we documented that Ang II-induced hypertrophic
remodeling and arterial stiffness were partly reduced by
chronic administration of COX-1 selective inhibitor SC-560,
or by the TP receptor blockade, while not being affected
by the COX-2 inhibitor DFU, thus indicating that COX-1,
but not COX-2, contributes to the pathogenesis of vascular
structural and mechanical changes elicited by Ang II [49].
These findings, obtained by a pharmacological approach,
were strongly substantiated by results from COX-1-KO mice,
in which Ang II failed to elicit vascular remodeling or
International Journal of Hypertension 5

Angiotensin II
Acetylcholine Acetylcholine
Arachidonic
NAD(P)H ? ?
Acid
Oxidase
L-arginine ↓ COX-2 ↑ COX-1

eNOS
PGH2
↑ ROS
NO

Endoperoxides
ONOO−

Reduced NO-mediated Increased TP-mediated

Relaxtion Contraction

Figure 1: Hypothetic involvement of cyclooxygenase (COX) isoforms in angiotensin II- (AngII-) induced endothelial dysfunction. Ang II
promotes reactive oxygen species (ROS) generation by vascular NAD(P)H oxidase activation. ROS rapidly react with nitric oxide (NO),
leading to reduce its availability and to produce peroxynitrites (ONOO− ). Ang II might also directly downregulate COX-2 or upregulate
COX-1. COX-1 is also activated by acetylcholine. Under such conditions, ROS stimulate COX-1 to transform arachidonic acid into
endoperoxides, which in turn activate the contracting thromboxane-prostanoid (TP) receptors.

mechanical changes. In the same context, a significant role of
the COX-1 pathway in Ang II-induced vascular ECM changes
emerged. Indeed, the enhanced deposition of collagen and
fibronectin was reduced by SC-560 and, to a similar extent,
by the TP receptor antagonist, while not affected by DFU.
In parallel, the vascular content of elastin was completely
restored by COX-1 and TP receptor blockade, while not
being ameliorated by COX-2 inhibition. In vessels from
COX-1− /− mice, collagen, fibronectin, and elastin contents
did not differ from wild type, and they were not modified
by Ang II [49]. Overall, these findings unequivocally support
a relevant role of COX-1-dependent TP receptor activation
in the development of Ang II-induced hypertrophic vascular
remodeling, changes in mechanics and ECM components,
leading to vascular fibrosis.
In conclusions, although a strict interaction between Ang
II and the COX pathway in the pathogenesis of vascular
injury is well established, the pivotal role of COX-1 or COX-
2 isoforms may differ and predominate according to the
experimental settings and the vascular districts considered.
There is also the possibility that in several vascular beds
a COX-1/COX-2 compensatory phenomenon occurs as a
consequence of Ang II stimulation, leading to different pat-
terns of prostanoid formation. Of course, the heterogeneous
experimental models, including both the variety of cells
stimulated and the different conditions in which Ang II
is applied, contribute to complicate the picture. For these
reasons, further experimental and clinical studies examining
the interaction between the renin-angiotensin system and
COX pathway are warranted.
O2 derivates, which play an active role in vascular biology.
ROS are generated within the vascular wall, at the level of
endothelial and vascular smooth muscle cells, as well as
by adventitial fibroblasts. In healthy conditions, ROS are
produced in a controlled manner at low concentrations
and function as signaling molecules regulating vascular
contraction-relaxation and cell growth. Physiologically, the
rate of ROS generation is counterbalanced by the rate of
elimination. Under pathological conditions, the ROS gen-
eration excess cannot be controlled by the usual protective
antioxidant mechanisms, leading to a state of oxidative stress.
A large body of evidence supports a crucial role for ROS
production, particularly from NAD(P)H oxidase, in vascular
injury which characterizes the hypertensive disease. Ang II
represents one of the major vasoactive peptides involved in
the regulation and activation of NAD(P)H oxidase. Ang II
stimulates activation of NAD(P)H oxidase, increases expres-
sion of NAD(P)H oxidase subunits, and induces ROS gener-
ation in vascular smooth muscle cells, endothelial cells, and
adventitial fibroblasts. A large body of evidence from exper-
imental and clinical studies unequivocally demonstrated
that Ang II exerts several pleiotropic deleterious vascular
effects, including functional and structural changes, through
NAD(P)H oxidase-derived ROS generation. More recently,
it was proposed that at the level of peripheral resistance
arteries, Ang II-mediated ROS production stimulates COX-
1 activity, to produce contracting prostanoids(s), acting as
agonists on TP receptors. Such mechanism likely contributes
to the endothelial dysfunction and vascular atherosclerotic
damage elicited by Ang II.

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